Piperine Suppresses Pyroptosis and Interleukin-1β Release upon ATP Triggering and Bacterial Infection

Abstract

Piperine is a phytochemical present in black pepper (Piper nigrum Linn) and other related herbs, possessing a wide array of pharmacological activities including anti-inflammatory effects. Previously, we demonstrated that piperine has therapeutic effects on bacterial sepsis in mice, but the underlying mechanism has not been fully elucidated. In this study, we aimed to investigate the influences of piperine on pyroptosis in murine macrophages. The results showed that piperine dose-dependently inhibited ATP-induced pyroptosis, thereby suppressing interleukin-1β (IL-1β) or high mobility group box-1 protein (HMGB1) release in LPS-primed bone marrow-derived macrophages and J774A.1 cells. Accompanying this, ATP-induced AMP-activated protein kinase (AMPK) activation was greatly suppressed by piperine, whereas AMPK agonist metformin counteracted piperine’s inhibitory effects on pyroptosis. Moreover, piperine administration greatly reduced both peritoneal and serum IL-1β levels in the mouse model intraperitoneally infected with Escherichia coli, suggestive of suppressing systemic inflammation and pyroptosis. Our data indicated that piperine could protect macrophages from pyroptosis and reduced IL-1β and HMGB1 release by suppressing ATP-induced AMPK activation, suggesting that piperine may become a potential therapeutic agent against bacterial sepsis.

Piperine Alleviates Doxorubicin-Induced Cardiotoxicity via Activating PPAR-γ in Mice

“…It is noteworthy that piperine could reduce the production of type I interferon and antagonize lipopolysaccharide-induced in ammatory responses [12]. Piperine also signi cantly inhibited the release of in ammatory factors and pyroptosis in lipopolysaccharide-primed macrophages by activating AMPactivated protein kinase [13]. e data in our lab demonstrated that piperine was a moderate agonist of PPAR-γ and could attenuate pathological cardiac brosis in mice [14].…”

Cyclic Stretch Negatively Regulates IL-1β Secretion Through the Inhibition of NLRP3 Inflammasome Activation by Attenuating the AMP Kinase Pathway

“…Previous studies reported that AMPK signaling was activated by a treatment with ATP through its binding to P2X7 receptors and has been shown to play a role in inflammasome activation ( Liang et al, 2016 ; Zha et al, 2016 ). We initially investigated the possible involvement of AMPK in our experimental system using a pharmacological inhibitor.…”

“…It regulates not only cellular metabolism, but also cell survival and proliferation ( Inoki et al, 2012 ). Recent studies reported that AMPK signaling is involved in ATP-induced inflammasome activation in LPS-primed macrophages, with the phosphorylated status of AMPK being enhanced by a stimulation with ATP ( Liang et al, 2016 ; Zha et al, 2016 ). In the present study, we showed that AMPK signaling had a similar contribution to that reported previously using compound C, a specific inhibitor of AMPK, and also that cyclic stretch inhibited ATP-induced AMPK phosphorylation, suggesting that the cyclic stretch-mediated inhibition of IL-1β secretion was partially due to the suppression of AMPK signaling.…”

AMP-Activated Protein Kinase and Host Defense against Infection

“…In Brucella abortus infection, AMPK activation enhances intracellular growth of B. abortus by inhibiting nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-mediated ROS generation [ 72 ]. In models of Escherichia coli sepsis, ATP-induced pyroptosis is blocked by piperine, a phytochemical present in black pepper ( Piper nigrum Linn) [ 73 ]. The inhibitory effects of piperine on pyroptosis and systemic inflammation are mediated by regulation of the AMPK signaling pathway, as shown by suppression of ATP-mediated AMPK activation by piperine treatment in vitro and in vivo [ 73 ].…”

“…In models of Escherichia coli sepsis, ATP-induced pyroptosis is blocked by piperine, a phytochemical present in black pepper ( Piper nigrum Linn) [ 73 ]. The inhibitory effects of piperine on pyroptosis and systemic inflammation are mediated by regulation of the AMPK signaling pathway, as shown by suppression of ATP-mediated AMPK activation by piperine treatment in vitro and in vivo [ 73 ]. These data suggest that AMPK plays multiple roles in bacterial infections.…”